ClinVar Miner

Submissions for variant NM_000383.4(AIRE):c.1616C>T (p.Pro539Leu)

gnomAD frequency: 0.00002  dbSNP: rs179363889
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000059052 SCV000329058 pathogenic not provided 2024-03-06 criteria provided, single submitter clinical testing Published functional studies demonstrate a reduction of transactivation activity compared to normal protein (PMID: 17675238); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21295522, 30018023, 15511668, 28446514, 23000069, 12398240, 17289071, 18713028, 15751604, 11836330, 15811934, 34846681, 17675238)
Counsyl RCV000409203 SCV000485843 likely pathogenic Polyglandular autoimmune syndrome, type 1 2016-02-25 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000409203 SCV000827161 pathogenic Polyglandular autoimmune syndrome, type 1 2023-09-08 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 68218). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on AIRE protein function. Experimental studies have shown that this missense change affects AIRE function (PMID: 17675238). For these reasons, this variant has been classified as Pathogenic. This missense change has been observed in individuals with autosomal recessive autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) (PMID: 11836330, 15811934, 17289071, 21295522, 28446514). This variant is present in population databases (rs179363889, gnomAD 0.006%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 539 of the AIRE protein (p.Pro539Leu).
Blueprint Genetics RCV000059052 SCV000927331 pathogenic not provided 2017-07-10 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000409203 SCV002797214 pathogenic Polyglandular autoimmune syndrome, type 1 2022-03-29 criteria provided, single submitter clinical testing
National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health RCV000409203 SCV004036196 pathogenic Polyglandular autoimmune syndrome, type 1 2023-09-14 criteria provided, single submitter clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center RCV000409203 SCV004806859 likely pathogenic Polyglandular autoimmune syndrome, type 1 2024-03-26 criteria provided, single submitter clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center RCV000409203 SCV005200788 likely pathogenic Polyglandular autoimmune syndrome, type 1 2024-05-15 criteria provided, single submitter clinical testing PS3, PM3, PM2, PP3
UniProtKB/Swiss-Prot RCV000059052 SCV000090573 not provided not provided no assertion provided not provided
PreventionGenetics, part of Exact Sciences RCV004754292 SCV005361284 pathogenic AIRE-related disorder 2024-09-27 no assertion criteria provided clinical testing The AIRE c.1616C>T variant is predicted to result in the amino acid substitution p.Pro539Leu. This variant has been reported, in the homozygous state or compound heterozygous state, in several patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) (Meloni et al. 2002. PubMed ID: 11836330; Perry et al. 2005. PubMed ID: 15811934; Meyer et al. 2007. PubMed ID: 17289071; Mazza et al. 2011. PubMed ID: 21295522; Zaidi et al. 2017. PubMed ID: 28446514, see Supplementary Table 1). The p.Pro539Leu change occurs at the first residue of the proline-rich PxxPxP motif (residues 539-544) at the very end of the C-terminus of the protein. The fourth LxxLL and the PxxPxP motifs at the C-terminus are critical for the transactivation capacity of the AIRE protein (Meloni et al. 2008. PubMed ID: 17675238). Meloni et al. showed that the p.Pro539Leu substitution resulted in a reduction of 77% in the transactivation activity. This variant has interpretations of Pathogenic and Likely Pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/68218/). In summary, the c.1616C>T (p.Pro539Leu) variant is categorized as pathogenic.

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